The Wnt signaling pathways are a group of signal transduction pathways made of proteins that pass signals into a cell through cell surface receptors. Three Wnt signaling pathways have been characterized: the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway.
All three pathways are activated by binding a Wnt-protein ligand to a Frizzled family receptor, which passes the biological signal to the Dishevelled protein inside the cell. The canonical Wnt pathway leads to regulation of gene transcription, and is thought to be negatively regulated in part by the SPATS1 gene.
The noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell. The noncanonical Wnt/calcium pathway regulates calcium inside the cell. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.
Crystal protein structure of Wnt8 and the cysteine-rich domain of Frizzled 8.Credit: Janda, C.Y., Waghray, D., Levin, A.M., Thomas, C., Garcia, K.C., via Wikimedia Commons
Wnt signaling was first identified for its role in carcinogenesis, then for its function in embryonic development. The embryonic processes it controls include body axis patterning, cell fate specification, cell proliferation and cell migration.
These processes are necessary for proper formation of important tissues including bone, heart and muscle. Its role in embryonic development was discovered when genetic mutations in Wnt pathway proteins produced abnormal fruit fly embryos.
Wnt signaling also controls tissue regeneration in adult bone marrow, skin and intestine. Later research found that the genes responsible for these abnormalities also influenced breast cancer development in mice.
This pathway’s clinical importance was demonstrated by mutations that lead to various diseases, including breast and prostate cancer, glioblastoma, type II diabetes and others. Encouragingly, in recent years researchers reported first successful use of with Wnt pathway inhibitors in mouse models of disease.
Discovery Of Wnt Signaling
The discovery of Wnt signaling was influenced by research on oncogenic (cancer-causing) retroviruses. In 1982, Roel Nusse and Harold Varmus infected mice with mouse mammary tumor virus in order to mutate mouse genes to see which mutated genes could cause breast tumors. They identified a new mouse proto-oncogene that they named int1 (integration 1).
Canonical Wnt pathwayCredit: Gpruett2 CC BY-SA 3.0
Int1 is highly conserved across multiple species, including humans and Drosophila. Its presence in D. melanogaster led researchers to discover in 1987 that the int1 gene in Drosophila was actually the already known and characterized Drosophila gene known as Wingless (Wg). Since previous research by Christiane Nüsslein-Volhard and Eric Wieschaus (which won them the Nobel Prize in Physiology or Medicine in 1995) had already established the function of Wg as a segment polarity gene involved in the formation of the body axis during embryonic development, researchers determined that the mammalian int1 discovered in mice is also involved in embryonic development.
Clinical Implications
Cancer
Since its initial discovery, Wnt signaling has had an association with cancer. When Wnt1 was discovered, it was first identified as a proto-oncogene in a mouse model for breast cancer. The fact that Wnt1 is a homolog of Wg shows that it is involved in embryonic development, which often calls for rapid cell division and migration. Misregulation of these processes can lead to tumor development via excess cell proliferation.
Canonical Wnt pathway activity is involved in the development of benign and malignant breast tumors. Its presence is revealed by elevated levels of β-catenin in the nucleus and/or cytoplasm, which can be detected with immunohistochemical staining and Western blotting. Increased β-catenin expression is correlated with poor prognosis in breast cancer patients.
This accumulation may be due to factors such as mutations in β-catenin, deficiencies in the β-catenin destruction complex, most frequently by mutations in structurally disordered regions of APC, overexpression of Wnt ligands, loss of inhibitors and/or decreased activity of regulatory pathways (such as the Wnt/calcium pathway). Breast tumors can metastasize due to Wnt involvement in EMT. Research looking at metastasis of basal-like breast cancer to the lungs showed that repression of Wnt/β-catenin signaling can prevent EMT, which can inhibit metastasis.
Wnt signaling has been implicated in the development of other cancers. Changes in CTNNB1 expression, which is the gene that encodes β-catenin, can be measured in breast colorectal, melanoma, prostate, lung, and other cancers. Increased expression of Wnt ligand-proteins such as Wnt 1, Wnt2 and Wnt7A were observed in the development of glioblastoma, oesophageal cancer and ovarian cancer respectively.
Other proteins that cause multiple cancer types in the absence of proper functioning include ROR1, ROR2, SFRP4, Wnt5A, WIF1 and those of the TCF/LEF family.
The link between PGE2 and Wnt suggests that a chronic inflammation-related increase of PGE2 may lead to activation of the Wnt pathway in different tissues, resulting in carcinogenesis.
Type II Diabetes
Diabetes mellitus type 2 is a common disease that causes reduced insulin secretion and increased insulin resistance in the periphery. It results in increased blood glucose levels, or hyperglycemia, which can be fatal if untreated. Since Wnt signaling is involved in insulin sensitivity, malfunctioning of its pathway could be involved.
Diagram illustrating the interaction between the Wnt and insulin signaling pathways.Credit: Yoon JC, Ng A, Kim BH, Bianco A, Xavier RJ, Elledge SJ CC BY-SA 3.0
Overexpression of Wnt5b, for instance, may increase susceptibility due to its role in adipogenesis, since obesity and type II diabetes have high comorbidity. Wnt signaling is a strong activator of mitochondrial biogenesis. This leads to increased production of reactive oxygen species (ROS) known to cause DNA and cellular damage.
This ROS-induced damage is significant because it can cause acute hepatic insulin resistance, or injury-induced insulin resistance. Mutations in Wnt signaling-associated transcription factors, such as TCF7L2, are linked to increased susceptibility.